The long-term goal of this project is to add a new dimension to our understanding of the mechanisms that regulate human urinary bladder function under normal and pathological conditions and to develop novel therapeutic strategies to control overactive bladder (OAB). OAB, detrusor overactivity (DO), and related urinary incontinence (UI), which affects about 17% of the US population, is characterized with increased urinary bladder smooth muscle (UBSM) contractility. Potassium ion (K+) channels, the most diverse ion channel superfamily, are key regulators of UBSM cell membrane excitability and action potentials that determine the phasic nature of UBSM contractility. In general, inhibition of these ion channels leads to increased membrane excitability and phasic contractions, whereas their activation hyperpolarizes the cell membrane and decreases contractility. Our basic science research group, in collaboration with clinical scientists, is in a unique position to regularly make use of human UBSM tissues from donor patients in order to study K+ channel function in humans and correlate the basic science findings with the urodynamic profile of the patients. The overall goal of this project is to illuminate the role of two major K+ channels, the small conductance Ca2+-activated (SK) K+ channel and the intermediate conductance Ca2+-activated K+ (IK) channel, and their regulatory mechanisms in human UBSM under normal and pathological conditions. This proposal will test the novel hypothesis that the SK/IK channels are major regulators of human UBSM excitability and contractility, and therefore changes in the SK/IK channels activity or regulatory mechanisms may lead to OAB/DO and related UI. Furthermore, the SK/IK channels may represent an opportunity for novel pharmacological manipulation and therapeutic intervention in human UBSM. Specific Aim 1 will elucidate the role of the SK/IK channels in UBSM function under normal and pathophysiological conditions;and Specific Aim 2 will elucidate the mechanism by which 2-adrenergic receptors signal the SK/IK channels to promote UBSM relaxation. This project will use UBSM tissues from patients with asymptomatic bladder (AUA symptom score <8;cystectomy for bladder cancer), OAB (defined as increased frequency, urgency, and nocturia), and DO (defined as urodynamically demonstrated overactivity). We will employ a combined approach, using state-of- the-art techniques, to determine the role of SK/IK channels and their regulatory mechanisms in UBSM function from single molecules and isolated cells to intact tissue and the whole organism. PUBLIC HEALTH RELEVANCE: Overactive bladder (OAB) affects about 17% of the US population, and is characterized by increased urinary bladder smooth muscle contractility. Our project will exploit specific potassium channels in urinary bladder tissue to develop novel therapies to control or alleviate OAB.